Method for the preparation of erythro vicinyl amino-alcohols

ABSTRACT

The present invention is concerned with the preparation of erythro N-substituted vicinal aminoalcohol derivatives from hydroxyl-protected cyanohydrin derivatives by successive Grignard reaction, transimination using a primary amine, reduction of the resulting imine and removal of the hydroxyl-protecting group. The products are obtained either as a racemate or in an optically pure form, depending upon the stereochemical composition of the cyanohydrin derivatives.

.Iadd.This application is a reissue of application 07/810,139, filedDec. 12, 1991 (U.S. Pat. No. 5,189,219). .Iaddend.

The present invention is concerned with a method for the preparation oferythro N-substituted vicinal amino-alcohol derivatives, and with thepreparation of intermediates for use in this method.

Vicinal amino-alcohol derivatives can be prepared according to Krepskiet at. (Synthesis 1986, 301) by reacting racemic silyl-protectedcyanohydrins with Grignard reagent, followed by a reduction step and adeprotection step. In general, poor stereoselectivity in the reductionstep was observed, resulting in erythro/threo mixtures of 1/1 to 24/1.

Optically pure hydroxy-protected cyanohydrins can be convened into thecorresponding victual amino-alcohol compounds using a similar procedure.Again, the method results in a rather poor chiral induction(erythro/threo ratios of 15/1 up to 24/1). As a result, N-substitutedcompounds prepared from these victual amino-alcohol compounds can not beobtained directly in a stereochemically pure form.

Furthermore, Brussee et at. (Tetrahedron Asymmetry 1, 163; 1990)describe the synthesis of some optically pure N-substituted vicinalamino-alcohol derivatives according to a lengthy procedure, by firstpreparing a protected alpha-hydroxyketone (acyloin) by Grignard reactionof the corresponding hydroxyl-protected cyanohydrin and subsequenthydrolysis of the Grignard-reacted product, whereafter the resultingacyloin was isolated from the reaction product. This hydroxyl-protectedacyloin was reacted in the second step with a primary amine to obtain anintermediate secondary imine, which was finally reduced to the desiredN-substituted hydroxyl-protected vicinal amino-alcohol. By theintroduction of magnesium ions and reduction at a low temperature (below0° C.) very high diastereoselectivity was achieved (erythro/threo ratiosabove 100/1).

According to the present invention an erythro N-substituted vicinalamino-alcohol derivative of formula 1 ##STR1## wherein

P is a group protecting the hydroxyl group;

R is a monocyclic or bicyclic aryl or heteroaryl group substituted withone or more groups X, wherein X is a hydroxy alkoxy(1-5C),alkyl(1-5C)carbonyloxy, amino, alkyl(1-5C)carbonylamino,alkyl(1-5C)sulphonylamino, nitro, alkyl(1-5C)sulphonyl,alkyl(1-5C)carbonyl, halogen, cyano, alkyl(1-5C), cycloalkyl(5-12C), ora cyclic group annelated with the aryl group or heteroaryl group, orwherein R is a saturated or unsaturated straight or branched alkyl grouphaving 1-30 C-atoms which may be substituted with halogen, alkoxy(1-5C),alkylthio(1-5C), phenyl or phenoxy optionally

R₁ and R₂ independently of each other are alkyl, alkenyl (2-8C), orphenyl or aralkyl(7-10C), optionally substituted with a group X isprepared without isolation of intermediate products by reacting ahydroxyl-protected cyanohydrin derivative of formula 2 ##STR2## with aGrignard reagent of formula 3

    R.sub.1 --Mg--Hal                                          (3)

yielding a Grignard reacted compound, followed by a novel transiminationreaction using a primary amine of formula 4

    R.sub.2 --NH.sub.2                                         ( 4)

and reduction of the resulting N-substituted imine, wherein P, R, R₁ andR₂ have the abovementioned meanings and Hal is a halogen atom.

The method according to the present invention avoids the lengthyprocedures from the prior art, and enables the stereoselectivepreparation of hydroxyl-protected N-substituted vicinal amino-alcoholderivatives in a one-pot reaction starting from the correspondinghydroxyl-protected cyanohydrins, without the need for isolation of anintermediate product.

Surprisingly it was found that the process according to the presentinvention gave a high yield with unexpectedly high stereochemicalinduction at ambient temperature.

According to the present invention pure erythro compounds can beobtained, starting from racemic cyanohydrins. Furthermore, starting fromoptically pure cyanohydrins, the pure erythro compounds are opticallypure too. This implies that during the latter reaction no racemisationof the cyanohydrin carbon atom occurs.

The final step in this preparation involves reduction of a compound offormula 5 ##STR3## wherein P, R, R₁ and R₂ have the aforementionedmeanings. This reduction can be established by the usual reagentsemployed for the conversion of imines into secondary amines, asdescribed by Harada in "The Chemistry of the Carbon-Nitrogen DoubleBond". pp. 276-293. Useful examples are (earth)alkali metalaluminumhydrides and borohydrides, (earth)alkali metals in proticsolvents, and hydrogen gas in the presence of a metal catalyst.Advantageously use is made of reagents of the general structure M₁ M₂(A)_(n) H_(4-n), wherein M₁ is a metal from the group IA or IIA of theperiodic system of elements, M₂ is boron or alumina, n is an integerhaving the value 0-3, and A is an electron-withdrawing substituent, e.g.of the type CN, halogen, alkoxy or dialkylamino. In particular, use canbe made of a reagent wherein M₂ is boron, n is 0 or 1 and A is CN.

The intermediate according to formula 5 is prepared by protonation ofthe Grignard reacted compound of formula 6 ##STR4## and the subsequenttransimination of the resulting imine with a primary amine of formula 4wherein P, R, R₁, R₂ and Hal have the aforementioned meanings. The abovereaction is novel, and the important advantage of this transformation isthat it is irreversible, resulting in a complete conversion ofN-unsubstituted imine into the N-substituted derivative.

Suitable hydroxyl-protecting groups P are for example silyl groups ofthe general formula 7

    --SiR.sub.3 R.sub.4 R.sub.5                                ( 7)

wherein R₃ to R₅ independently of each other can be alkyl or alkenylgroups having 1-8 carbon atoms, phenyl or aralkyl having 1-10 carbonatoms, a tertiary alkyl group having 4-12 carbon atoms, an alkoxyalkylgroup having 2-12 carbon atoms or the corresponding groups whereinoxygen is substituted by sulphur, or for example a dihydropyran-2-ylgroup, a tetrahydropyran-2-yl group, a dihydrofur-2-yl group or atetrahydrofur-2-yl group, which groups may be substituted with an alkylgroup having 1-6 carbon atoms, or the corresponding groups whereinoxygen is replaced by sulphur.

The compounds of formula 1 can be convened into the correspondingunprotected N-substituted ethanol-amines by removal of the protectinggroup P. This protecting group can be removed by methods known in theart.

The resulting N-substituted ethanolamines, either as racemates, or aspure enantiomers are for example useful as pharmaceutically activeagents. Examples of these are ephedrine, isoxsuprine, ritodrine,dilevalol, labetolol, sotalol, salbutamol and clenbuterol.

EXAMPLE 1(1R,2S)-(-)-2-(Methylamino)-1-phenyl-1-[(tert.butyldimethyl-silyl)oxy]-propane.

To a magnetically stirred solution of 72 mmol of CH₃ MgI in 125 ml ofether was added dropwise 12 g (48mmol) of(R)-(+)-[tert-butyldimethylsilyl)oxy]-benzeneacetonitrile in 100 ml ofanhydrous ether. After 4 hours reflux the excess of Grignard reagent wasdestroyed and the free imine was liberated by adding 50 ml of drymethanol. This was directly followed by a transimination reactioncomprising the addition of a solution of 96 mmol of methylamine in 50 mlof methanol. After stirring for 30 rain at room temperature the reactionmixture was cooled to 4° C. and 3.6 g (94 mmol) of NaBH₄ was added inthree portions. The reaction mixture was stirred overnight at roomtemperature. Water was added and the mixture was extracted with ether(3×150 ml). The combined organic layers were washed twice with brine,dried on K₂ CO₃ and evaporated.

Yield: 12.4 g (92.5%). NMR: 97% erythro, 3% threo.

Crystallization from absolute ethanol of this product as HCl saltafforded the pure captioned product. Analytical data were in completeagreement with the literature.

EXAMPLE 2 (1R,2S)-(-)-2-(Methylamino)-1-phenyl-1-propanol,HCl(Ephedrine.HCl).

Deprotection of the compound prepared according to Example 1 (12.3 g)was performed with LiAlH₄ in THF. The crude product (8.1 g contaminatedwith TBSOH) was dissolved in 100 ml of anhydrous ether and cooled in anice bath. Dry HCl gas was passed until the amine was neutralized. Theprecipitate was filtered off, washed with anhydrous ether and dried.

Yield: 7.4 g (83%) ephedrine.HCl. Analytical data were identical tothose of an authentic sample.

EXAMPLE 3(1R,2S)-(-)-2-(Benzylamino)-1-phenyl-1-(tert.butyldimethyl-silyl)oxy]-propane.

The captioned compound was prepared in the same manner as described inExample 1, using benzylamine in the transimination reaction.

Yield: 94%. NMR: 98% erythro, 2% threo.

Crystallization from absolute ethanol as HCl salt afforded the purecaptioned product. Analytical data were in complete agreement withliterature.

EXAMPLE 4 (1R,2S)-(-)-2-(Benzylamino)-1-phenyl-1-propanol, HCl.

Prepared as described in Example 2 starting from the product obtainedaccording to Example 3.

Yield: 89%.

¹ H NMR (220 MHz, MeOD, ppm): 7.2-7.6 (m, 10H, arom); 5.26 (d, 1H, J=3.1Hz, HOCH); 4.37 (s, 2H, CH₂ C₆ H₅); 3.50 (m, 1H, HCCH₃); 1.10 (d, 3H,J=6.7 Hz, CH₃).

[α]₀ =11.5° (c=1, MeOH), mp: 194°-195° C. Analytical data identical tothose of a sample prepared by a method described in the literature.

EXAMPLE 5(1R,2S)-(-)-2-(2-Phenylethylamino)-1-phenyl-1-[(tert.butyl-dimethylsilyl)oxy]-propane.

The captioned compound was prepared in the same manner as described inExample 1, using phenylethylamine in the transimination reaction.

Yield: 98%. NMR: 98% erythro, 2% threo.

Crystallization from absolute ethanol as HCI salt afforded the purecaptioned compound. Analytical data were in complete agreement withthose reported in the literature.

EXAMPLE 6

(1R,2S)-(-)-2-(2-Phenylethylamino)-1-phenyl-1propanol,HCl.

Prepared as described in Example 2 starting from the product obtainedaccording to Example 5.

Yield: 87%.

¹ H NMR (220 MHz, MeOD, ppm): 7.2-7.6 (m, 10H, arom); 5.21 (d, 1H, J=3.1Hz, HOCH); 3.53 (m, 1H, HCH₃); 3.32 (m, 2H, CH₂); 3.09 (m, 2H, CH₂);1.08 (d, 3H, J=6.7 Hz, CH₃). [α]_(D) =16.4° (c=1, MeOH), mp: 203°-205°C. Analytical data identical to those of a sample prepared from(1R,2S)-norephedrine and phenylacetaldehyde by a method described in theliterature.

EXAMPLE 7

Ritodrine was synthesized according to the following scheme: ##STR5## 25g of p-hydroxybenzaldehyde (compound 7-1) was dissolved in 55 ml ofacetic acid en 38 ml of tetrahydrofuran (THF). Sodiumcyanide (43 g),dissolved in 70 ml of water, was added in 10 minutes while thetemperature was kept at 20° C. After stirring for 4 hours, the reactionmixture was diluted with water en extracted with diethylether. Thecombined ether layers were washed with saturated NaCl solution, dried onNa₂ SO₄ and evaporated at 35° C. The residu (32.8 g) contains compound7-2

NMR(DMSO): 5.53(d,1H); 6.79(m.2H); 7.28(d,2H); 9.60(5,1H)

Trimethylsilyl chloride (12.4 g) was added to a solution of 9.4 g ofimidazole in 85 ml of dry ethylacetate. After stirring for 15 minutes,5.63 g p-hydroxymandelonitril was added. Stirring was continuedovernight, and then the reaction mixture was washed thoroughly withwater. The water layers were extracted with ethylacetate and thecombined ethylacetate layers were dried on Na₂ SO₄ and molecular sieves.Ethylacetate was evaporated to give 10.42 g of residu, that contained8.1 g of compound 7-3

NMR (CDCl₃): 0.23(s,9H); 0.27(s,9H); 5.44 (s,1H); 6.88 (d,2H);7.34(d,2H).

Conversion of compound 7-3 to ritodrine: To a solution of 8 ml of etherand 2 ml 3 mol/l CH₃ MgI in ether was added 1 g of compound 7-3 in 7 mlof ether. The solution was stirred overnight and a white precipitate wasformed. Then 8 ml of dry methanol was added, followed by addition of 0.7g of tyramine (=4-(2-aminoethyl)phenol). Stirring was continued for 24hours. Then 0.26 g of NaBH₄ was added in several portions and thereaction mixture was stirred for another 24 hours. The mixture washydrolysed by adding 20 ml 4 N HCl. After 4 hours the solution isbrought to pH=7 by addition of NaOH pellets. The solution containedritodrine as monitored by HPLC; the ratio erythro/threo was about 7.5/1.Part of the solution was evaporated. The residu was treated withmethanol and filtrated. The filtrate was evaporated and the residu wasanalyzed by NMR, demonstrating the presence of ritrodrine. HCl

NMR (DMSO/CDCl₃ 5/1): 0.97 (d,3H); 2.92 (bt,2H); 3.31 (bm, 1H); 5.08(bS, 1H); 5.94 (bd, 1H); 6.73 (d,2H); 6.76 (d,2H); 7.05 (d,2H); 7.16(d,2H); 8.85 (bs,2H); 9.30 (s,1H); 9.35 (s,1H)

EXAMPLE 8

The ritodrine-derivative 8-6 was synthesized according to the followingscheme: ##STR6## Compound 8-1 was transformed into compound 8-2according to the corresponding reaction as described in Example 7. Thecyanohydrine 8-2 was protected in the following way: 12.6 g oftert.butyldimethylsilylchloride was dissolved in 25 ml of ethylacetateand added to a solution of 6.3 g of imidazole in 80 ml of ethylacetate.After 15 minutes 5 g of p-hydroxy-mandelonitril (compound 8-2) in 25 mlor ethylacetate was added and stirring was continued for 22 hours. Waterwas added and the organic layer was washed three times with water. Afterdrying on NazSO<and molecular sieves, ethylacetate was evaporated togive 11.3 g residu, containing 89% of compound 8-3 according to NMR.

NMR (CDC₁₃): 0.11 (s,3H); 0.19 (s,3H); 0.20 (s,6H);

0.91 (s,9H); 0.98 (s,9H);

5.44 (s,1H); 6.85 (d,2H); 7.31 (d,2H).

Conversion of 8-3 into ritodrine-derivative 8-6.

To a solution of 15 ml of ether and 4 ml 3 mol/l of CH₃ MgI in ether wasadded 2.7 g of compound 8-3 in 18 ml of ether, The solution was stirredfor 22 hours. Under cooling, 20 ml of dry methanol was added, followedby 1.6 gram of benzyltyramine. The reaction mixture was stirred for 24hours and then 0.54 g of NaBH₄ was added in small portions whilecooling. After stirring for another 24 hours, 20 ml of 4N HCl was addedwhile cooling. The reaction mixture was subsequently made alkaline(pH>9) by the addition of sodiumhydroxide solution. The precipitate wasfiltered off, the organic ether layer was washed neutral with water anddried. Evaporation of the solvent yielded 3.52 g of residu, containingthe ritodrine-derivative 8-6 as a free base.

NMR (CDCl₃):-b 0.03 (s,3H); 0.09 (s,3H); 0.17 (s,6H); 0.84 (s,9H); 0.97(s,9H); 1.03 (d,3H); 2.55-2.77(m,2H+1H); 2.86 (m,2H); 4.48 (d,1H); 5.02(s,2H); 6.76 (d,2H); 6.86 (d,2H); 7.02 (d,2H); 7.11 (d,2H); 7.30-7.46(m,5H).

We claim:
 1. Method for the preparation of an erythro N-substitutedvicinal amino-alcohol derivative of formula 1 ##STR7## wherein P is agroup protecting the hydroxyl group;R is a monocyclic or bicyclic arylor heteroaryl group substituted with one or more groups X, wherein X isa hydroxy, alkoxy(1-5C), alkyl(1-5C)carbonyloxy, amino,alkyl(1-5C)carbonylamino, alkyl(1-5C)sulphonylamino, nitro,alkyl(1-5C)sulphonyl, alkyl(1-5C)carbonyl, halogen, cyano, alkyl(1-5C),cycloalkyl(5-12C), or a cyclic group annelated with the aryl group orheteroaryl group, or wherein R is a saturated or unsaturated straight orbranched alkyl group having 1-30 C-atoms which may be substituted withhalogen, alkoxy(1-5C), alkylthio(1-5C), phenyl or phenoxy optionallysubstituted with one or more groups X, and R₁ and R₂ independently ofeach other are alkyl, alkenyl (2-8C), or phenyl or aralkyl(7-10C),optionally substituted with a group X by reacting a hydroxyl-protectedcyanohydrin derivative of formula 2 ##STR8## with a Grignard reagent offormula 3

    R.sub.1 --Mg--Hal                                          (3)

yielding a Grignard reacted compound, followed by a novel transiminationreaction using a primary amine of formula 4

    R.sub.2 --NH.sub.2                                         ( 4)

and reduction of the resulting N-substituted imine, wherein P, R, R₁ andR₂ have the abovementioned meanings and Hal is a halogen atom.
 2. Methodaccording to claim 1 wherein use is made of one of the .[.enatiomers.]..Iadd.enantiomers .Iaddend.of the compound of formula 2 thereby yieldingan optically pure erythro derivative of the compound according toformula
 1. 3. Method for the preparation of a compound of formula 8##STR9## by using the method according to claim 1 or 2 and subsequentlyremoving the hydroxyl-protecting group P of the compound of formula 1,wherein P, R, R₁, and R2 have the abovementioned meanings. .Iadd. 4.Method for the preparation of an erythro N-substituted vicinalamino-alcohol derivative of formula 1 ##STR10## wherein P is a groupprotecting the hydroxyl group;R is an unsubstituted monocyclic orbicyclic aryl or heteroaryl group or a cyclic group annelated with thearyl group or heteroaryl group, and R₁ and R₂ independently of eachother are alkyl, alkenyl (2-8C), or phenyl or aralkyl(7-10C), optionallysubstituted with a group X by reacting a hydroxyl-protected cyanohydrinderivative of formula 2 ##STR11## with a Grignard reagent of formula 3

    R.sub.1 --Mg--Hal                                          (3)

yielding a Grignard reacted compound, followed by a novel transiminationreaction using a primary amine of formula 4

    R.sub.2 --NH.sub.2                                         ( 4)

and reduction of the resulting N-substituted imine, wherein P, R, R₁ andR₂ have the abovementioned meanings and Hal is a halogen atom. .Iaddend..Iadd.
 5. Method according to claim 4 wherein use is made of one of theenantiomers of the compound of formula 2 thereby yielding an opticallypure erythro derivative of the compound according to formula 1..Iaddend. .Iadd.6. Method for the preparation of a compound of formula 8##STR12## by using the method according to claim 4 or 5 and subsequentlyremoving the hydroxyl-protecting group P of the compound of formula 1,wherein P, R, R₁, and R₂ have the abovementioned meanings. .Iaddend.